The need to treat elusive and debilitating disorders such as cancer, rheumatoid arthritis, diseases involving undue inflammation or proliferation, osteoporosis and other diseases involving untoward bone resorption (e.g., Paget's Disease, primary and secondary hyperparathyroidism, humoral hypercalcemia of malignancy, and various cancers where bone resorption is increased), restenosis following coronary angioplasty, glomerulonephritis, glomerulosclerosis, liver cirrhosis, pulmonary fibrosis, disorders involving increased vascular permeability, and others, has led to extensive research on the mechanisms involved in disease initiation and/or progression and on the identification of new drugs which might interfere with those mechanisms.
Cellular signal transduction mediated by kinases is believed to play a key role in in cell proliferation, carcinogenesis and cell differentiation and in a wide variety of diseases, including those mentioned herein.
Several families of protein tyrosine kinases which have been implicated in human cancer and other diseases, include among many others, Src, Abl, Jak, Ack, Csk, Fak, Fes, Frk, Tec, and Syk. See. e.g., Blume-Jensen et al. Nature, 2001, 411, 355, and references cited therein.
Although some progress has been made towards developing therapeutic agents for a variety of disorders mentioned herein, there remains a need for new therapeutic agents which have desirable functional characteristics such as in vitro or in vivo potency, selectivity profile, ClogP, aqueous solubility, ability to penetrate cells, etc.,—or from an more global viewpoint, which have a beneficial therapeutic index, have a useful pharmacokinetic profile, have a desirable specificity of action, have reduced untoward side effects, may be given to patients who cannot well tolerate or do not respond sufficiently to existing therapies, and/or may be used in conjunction with other therapies.